The cerebral cortex is critically important for higher motor, sensory, and cognitive functions of the brain, such as social interactions and communication, and together with subcortical areas of the limbic system, regulate complex emotional and motivated behaviors. Disorders of cortical development underlie neuropsychiatric illnesses such as autism, schizophrenia, and depression, and the abnormal developmental trajectories of cortical and limbic circuits may impact adaptive behaviors such as drug abuse. The objective of this proposal is to investigate the molecular and cellular mechanisms regulating the normal production of neurons in the cerebral cortex, which arise from a heterogeneous population of stem/progenitor cells located in the ventricular zone of the neocortex and essential for correct neural circuit trajectories. Cell-cell interactions mediated by Delta-Notch signaling are required for both producing the correct number of neurons and maintaining the progenitor pool during corticogenesis, although essential details remain unknown. Importantly, the specific cellular and molecular interactions between different cell types have not been delineated. We hypothesize that different cell types signal to each other through evolutionary diversified components of Delta-Notch gene families, and that a novel Delta-mediated interaction between a subset of progenitors controls the balance between neuron production and progenitor maintenance. We will first determine the cortical cell types that express different Delta-Notch signaling components using combined in situ hybridization/immunolabeling techniques in conjunction with transgenic markers of defined cell types. We have developed a novel 2-color 2-photon live-cell imaging technique that serves as major innovation, allowing us to determine the cellular basis of Delta-Notch signal transduction in dynamically behaving cells that will be tested in functional experiments. The results of this exploratory R21 grant will provide the foundation of a sophisticated new model we propose that encompasses multiple sources of cell-cell interactions regulated by diverse Delta-Notch signaling in the developing cortex. Future studies will examine this mechanism in developing subcortical regions, and in adolescent and adult neurogenesis. PUBLIC HEALTH RELEVANCE: Neurological and behavioral diseases and disorders, such as autism, schizophrenia and susceptibility to drug abuse are thought to arise from developmental deficits in the generation/trajectory/connectivity of neurons in the brain. If we know how these neurons normally develop, then we will be better able to develop strategies aimed at repairing or replacing them when their normal development goes awry.